Receptors for the Fc region (FcRs) of Igs have broad tissue distribution patterns and can modulate cellular and humoral immunity by linking their antibody ligands with effector cells of the immune system (Ravetch, J. V. & Kinet, J.-P. (1991) Annu. Rev. Immunol. 9, 457-492; Daeron, M. (1997) Annu. Rev. Immunol. 15, 203-234. These cellular receptors have the ability to sense humoral concentrations of antibody, initiate cellular responses in host defense, and participate in autoimmune disorders (Ravetch, J. V. & Bolland, S. (2001) Annu. Rev. Immunol. 19, 275-290). Their diverse regulatory roles depend on the Ig isotype specificity and cellular distribution of the individual FcR. These Ig superfamily members share similarities in their ligand binding subunits, and they may have inhibitory or activating signaling motifs in their intracellular domains or instead pair with signal transducing subunits possessing activating signaling motifs.
Recently, characterization of FcR homologs in mice, the paired Ig-like receptors (Kubagawa, H. et al. (1997) Proc. Natl. Acad. Sci. USA 94, 5261-5266; Hayami, K. et al. (1997) J. Biol. Chem. 272, 7320-7327), and their relatives in humans the Ig-like transcripts/leucocyte Ig-like receptors (Borges, L. et al. (1997) J. Immunol. 159, 5192-5196; Samaridis, J. & Colonna, M. (1997) Eur. J. Immunol. 27, 660-665) have been elucidated. This multigene family, which includes the FcαR (Kremer, E. J. et al. (1992) Hum. Genet. 89, 107-108) and the natural killer cell Ig-like receptors (Wagtmann, N. et al. (1997) Curr. Biol. 7, 615-618), is located in a human chromosome 19q13 region known as the leucocyte receptor complex (LRC) (Wende, H. et al. (1999) Mamm. Genome 10, 154-160; Wilson, M. J. et al. (2000) Proc. Natl. Acad. Sci. USA 97, 4778-4783). These Ig-like multigene families belong to a larger class of receptors characterized by their possession of common cytoplasmic tyrosine-based signaling motifs. These can be either immunoreceptor tyrosine-based activation motifs (ITAMs) containing two repeats of the consensus sequence Y-X-X-L/I spaced by 6-8 amino acids (E/D)-X-X-Y-X-X-(L/I)-X6-8-Y-X-X-(L/I) (SEQ ID NO:64, with six amino acid between the consensus sequences; SEQ ID NO:65, with seven amino acid residues between the consensus sequences; and SEQ ID NO:66, with eight amino acid residues between the consensus sequences) or immunoreceptor tyrosine-based inhibitory motifs (ITIMs) with a 6-amino acid consensus sequence (I/V/L/S)-X-Y-X-X-(L/V) (SEQ ID NO:67) (Reth, M. (1992) Annu. Rev. Immunol. 10, 97-121; Vely, F. & Vivier, E. (1997) J. Immunol. 159, 2075-2077; Ravetch, J. V. & Lanier, L. L. (2000) Science 290, 84-89; Gergely, J. et al. (1999) Immunol. Lett. 68, 3-15). The phylogenetic conservation of these types of receptors in birds (Dennis, G. et al. (2000) Proc. Natl. Acad. Sci. USA 97, 13245-13250) and bony fish (Yoder, J. A. et al. (2001) Proc. Natl. Acad. Sci. USA 98, 6771-6717) is indicative of their biological value. After ligand binding of the activating receptor complexes, ITAM tyrosines are rapidly phosphorylated by Src family kinases to initiate a cascade of signaling events that trigger cellular activation. In the case of ITIM-bearing receptors, the tyrosines provide a docking site for phosphatases containing Src homology 2 domains that can abrogate cellular activation (Long, E. O. (1999) Annu. Rev. Immunol. 17, 875-904; Unkeless, J. C. & Jin, J. (1997) Curr. Opin. Immunol. 9, 338-343). The balance in the utilization of these activating and inhibitory receptor pairs can serve to modulate cellular responses to a variety of stimuli.
The genes encoding the classical FcγRs, FcγRI, FcγRII, FcγRIII, and FcεRI, lie on the long arm of chromosome 1 (1q21-23) near the polymeric Ig receptor (pIgR) and Fcα/μR genes (1q32) (20-23). Members of this FcR subfamily have relatively low extracellular homology with the FcR-related genes that reside in the LRC on chromosome 19. Like the FcγR- and FcεR-activating receptors, the ligand binding chain of the FcαR coassociates with the ITAM containing FcR common γ-chain (Pfefferkorn, L. C. & Yeaman, G. P (1994) J. Immunol. 153, 3228-3236; Morton, E. C. et al. (1995) J. Biol. Chem. 270, 29781-29787). New members of the FcR family were sought which could have diverse signally properties and oncogenic potential.